The long-term goal of this research is to determine the molecular/cellular basis for the gene- environment interactions in the pathogenesis of skin cancer. The major environmental risk factor for non-melanoma skin cancer is ultraviolet (UV) radiation in sunlight including UVB and UVA. Although UVA has different physical and biological targets from UVB, the UVA contribution to skin cancer susceptibility and its molecular basis is unclear. Preliminary data within this proposal demonstrate that a critical suppressor for human and mouse skin cancer is PTEN (phosphatase and tensin homologue deleted on chromosome 10). In epidermal keratinocytes, PTEN transcription is significantly down-regulated by UVA, whereas targeted deletion of PTEN in the epidermis accelerates skin carcinogenesis. Although the precise mechanisms responsible for the enhanced susceptibility to skin tumorigenesis are unknown, preliminary data within this proposal show that PTEN loss may impair repair and checkpoints in response to DNA damage. The central hypothesis of the proposed experiments is that UVA-induced down-regulation of PTEN transcription inhibits DNA repair and DNA damage checkpoints and thus increases skin cancer susceptibility. The overall aim of this proposal is to determine the molecular mechanisms and consequences of UVA-induced PTEN down-regulation. The specific aims are to (1) test the hypothesis that PTEN down-regulation inhibits DNA repair and DNA damage checkpoints in response to low-level UV irradiation; (2) elucidate upstream regulators critical for UVA-induced down-regulation of PTEN transcription; and (3) analyze the consequences of PTEN down- regulation in skin cancer susceptibility in vivo. These experiments will provide new insights into the molecular and cellular basis for the UVA contribution to skin carcinogenesis. This knowledge can be used to develop better strategies to prevent and treat skin cancer.